JPH037291A - 3'-hydroxybenzoxadinorifamycin derivative - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I [R is H or acetyl; A is formula II (R<1> is 4-8C alkyl, 2-8C alkenyl, 2-8C alkynyl, 1-4C aminoalkyl, 2-6C monoalkylaminoalkyl, etc.), formula III (b is 2-6) or formula IV (n is 2-6; R<3> is amino, 1-6C monoalkylamino, 1-6C acylamino, etc.)]. USE:An antibacterial agent. PREPARATION:With a rifamycin derivative represented by formula V an amine expressed by formula AH is reacted.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel famycin derivative or a salt thereof, a method for producing the same, and an antibacterial agent containing the same as an active ingredient. More specifically, the present invention relates to formula (I): [blank below] 8 alkyl group, C2-8 alkenyl group, C2-8 alkynyl group, C1-4 aminoalkyl group, carbon Monoalkylaminoalkyl group having 2 to 6 carbon atoms, dialkylaminoalkyl group having 3 to 8 carbon atoms, 2 to 6 carbon atoms
8 alkoxyalkyl group, alkoxyalkyloxyalkyl group having 3 to 8 carbon atoms, thioalkoxyalkyl group having 2 to 6 carbon atoms, dialkoxyalkyl group having 3 to 8 carbon atoms, halogenated alkyl group having 1 to 6 carbon atoms , carbon number 1~
6 acyl group, a group represented by the formula: (CH2) -CONHR2 (in the formula, a represents an integer of θ to 3, and further R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), a hydrocarbon a new famycin derivative or a salt thereof, and a method for producing the same; The present invention relates to an antibacterial agent containing a rifamycin derivative or a pharmacologically acceptable salt thereof as an active ingredient.

[Prior Art/Problems to be Solved by the Invention] The rifamycin derivative according to the present invention is a novel compound that has not been described in any literature.

In order to find a new and excellent antibacterial agent, the present inventors developed the formula (
I): A group or formula represented by (wherein b represents an integer of 2 to 6): (wherein n represents an integer of 2 to 6, and further R3 is an amino group, a group having 1 to 6 carbon atoms) Monoalkylamino group, carbon number 2~
A novel rifamycin derivative having 10 dialkylamino groups (wherein R and A are the same as above) was synthesized, and its antibacterial activity and pharmacological properties were investigated. As a result, the inventors discovered that the novel rifamycin derivative represented by formula m has a strong antibacterial effect and excellent pharmacological properties, and arrived at the present invention.

[Means for Solving the Problems] The present invention is based on the formula (I): (wherein R represents a hydrogen atom or an acetyl group, an alkyl group having 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, 8 alkynyl group, aminoalkyl group having 1 to 4 carbon atoms, monoalkylaminoalkyl group having 2 to 6 carbon atoms, 3 to 4 carbon atoms
8 dialkylaminoalkyl group, alkoxyalkyl group having 2 to 8 carbon atoms, alkoxyalkyloxyalkyl group having 3 to 8 carbon atoms, thioalkoxyalkyl group having 2 to 6 carbon atoms, dialkoxyalkyl group having 3 to 8 carbon atoms , a halogenated alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, formula = (CI+2) -CONHR2 (in the formula, a
represents an integer of θ to 3, and R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; b is 2
(Representing an integer of 2 to 6) or formula: (In the formula, n represents an integer of 2 to 6, and R3 is an amino group, a monoalkylamino group having 1 to 6 carbon atoms, or a group having 2 to 6 carbon atoms.)
10 dialkylamino group or C1-6 acylamino group) or a salt thereof, a novel rifamycin derivative or a salt thereof, formula (I):
Formula (I), characterized in that a rifamycin derivative represented by the formula (wherein R represents a hydrogen atom or an acetyl group) is reacted with an amine represented by the formula AH (wherein A is the same as above) The present invention relates to a method for producing a rifamycin derivative represented by formula (I) or a salt thereof, and an antibacterial agent containing the rifamycin derivative represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

The novel rifamycin derivative represented by the formula (I) according to the present invention can be used in many organic solvents, halogenated hydrocarbons such as chloroform; alcohols such as ethyl alcohol; esters such as ethyl acetate; and aromatic compounds such as benzene. Hydrocarbons: Soluble in ethers such as tetrahydrofuran.

Specific examples of the substituent A of the novel rifamycin derivative represented by formula (I) according to the present invention include -N NL; 'diH2L:1I2U L; as a group represented by t13 (in the formula, b is the same as above) (in the formula, n and R3
is the same as above) as a group represented by -1C1/-NHz -'ZN (C)13) 2
The novel rifamycin derivative represented by formula (I) according to the present invention can form a salt with either a base or an acid. As the base or acid that can be used to form a salt, any base or acid that can be used to form a salt with the rifamycin derivative represented by formula (I) can be selected. Specific examples of salts with bases include (I) metal salts, especially salts with alkali metals and alkaline earth metals, (2) ammonium salts, and (3) amine salts, especially methylamine, ethylamine, diethylamine, and triethylamine. , pyrrolidine, morpholine, hexamethyleneimine, etc. Examples of salts with acids include (I) salts with mineral acids such as sulfuric acid and hydrochloric acid, and salts with organic acids such as (2p-)luenesulfonic acid, trifluoroacetic acid and acetic acid.

The novel rifamycin derivative represented by the formula m according to the present invention can be produced as follows.

That is, (A) 3'-hydroxybenzoxazinorifamycin synthesized by the method described in U.S. Pat.
When dissolved in an organic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, and at a temperature from -20°C to the boiling point of the solvent, the formula AI! (In the formula, A is the same as above) in the presence or absence of an acid such as hydrochloric acid,
It can be obtained by reacting for 1 hour to 1 month in the presence or absence of an oxidizing agent such as manganese dioxide.

The rifamycin derivative represented by formula (If) is 1
0.5 to 10 of the amine represented by the formula All per mole
Good results can be obtained by using moles, especially 1 to 3 moles.

Reaction solvents include methanol, ethanol, isopropyl alcohol, tetrahydrofuran, pyridine, acetone, ethyl acetate, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, N-methyl-2- Pyrrolidone, dimethyl sulfoxide, etc. can be used, but pyridine, N,N-dimethylformamide, N,N
- Better results can be obtained using dimethylacetamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc. The reaction temperature can be selected from -20°C to the boiling point of the solvent, but from -5°C to 50°C.
Better results can be obtained if the reaction is carried out at ℃. The reaction time is approximately 1 hour to 1 month, but the optimal reaction time varies depending on the reaction conditions such as the type and amount of amine used in the reaction, the presence or absence of an oxidizing agent, type and amount, and reaction temperature. should be determined by tracking with thin layer chromatography. In the reaction carried out in the presence of an oxidizing agent, examples of the oxidizing agent that can be used include air, oxygen, manganese dioxide, lead dioxide, silver oxide, potassium ferricyanide,
There are hydrogen peroxide, but better results can be obtained by choosing manganese dioxide, silver oxide, potassium ferricyanide, etc.

(B) The rifamycin derivative represented by the formula (I) shown below is replaced with the rifamycin derivative represented by the formula (II) used in the method described in (A).

(A) using a rifamycin derivative represented by E] It can be synthesized according to the method described.

Synthesis conditions such as reaction solvent and reaction temperature may be the same as those described in the synthesis method (^).

The rifamycin derivative represented by formula (2), which is the starting material for this synthesis method, is prepared by combining rifamycin S and a compound represented by the formula: (wherein X is the same as above) in US Patent Section 4. (i
It can be obtained by reacting according to the method for synthesizing 3'-hydroxybenzoxazinorifamycin described in No. 90.919.

A rifamycin derivative represented by formula (I) in which R is hydrogen can also be obtained by hydrolyzing a rifamycin derivative represented by formula (I) in which R is an acetyl group using an acid or a base. . Examples of acids that can be used for hydrolysis include mineral acids such as sulfuric acid and hydrochloric acid, and organic acids such as p-toluenesulfonic acid and trifluoroacetic acid.

Bases that can be used similarly include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; l,5-diazabicyclo[4,3 ,0] non-5
There are basic bases such as -ene, 8-diazabicyclo[5,4,0]undec-7-ene, etc. Good results can be obtained by carrying out the reaction at room temperature using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and a solvent such as aqueous methanol or aqueous pyridine.

Although the rifamycin derivative represented by formula (I) according to the present invention is a dark purple solid, it is relatively easy to separate and purify it from the reaction product. That is, the excess amount of the amine represented by the formula A11 (in the formula, A is the same as above) used in the reaction, the reaction solvent, etc. is removed, and the resulting crude product is purified by crystallization, column chromatography, etc. , the desired rifamycin derivative can be obtained.

The novel rifamycin derivative represented by formula (I) can be prepared by reducing it with a reducing agent such as ascorbic acid or sodium hydrosulfide, resulting in the following: [blank below] 4' (wherein R and A are the same as above) It is also possible to convert it into a rifamycin derivative represented by The rifamycin derivative represented by formula N is also new and has strong antibacterial activity.

Representative examples of novel rifamycin derivatives according to the present invention are shown in the first example.
Shown in the table. In Table 1, infrared absorption spectra were measured using the potassium bromide tablet method. Thin layer chromatography was performed using silica gel 130F manufactured by Merck and a plate for thin layer chromatography 54 (20 cs x 20 cm).

Nuclear magnetic resonance spectra were measured using a deuterated chloroform solution of the sample with tetramethylsilane as an internal standard.

[Margins below] The rifamycin derivative according to the present invention exhibits strong antibacterial activity against Durham-positive bacteria and acid-fast bacteria.

The antibacterial activity of the novel rifamycin derivative according to the present invention was evaluated using the standard method of the Japanese Society of Chemotherapy [Journal of the Japanese Society of Chemotherapy, Vol. 29,
76 (I981)]. Representative examples are shown in Table 2. As is clear from Table 2, the novel rifamycin derivatives of the present invention exhibit strong antibacterial activity against Durham-positive bacteria and acid-fast bacteria. Note that the derivative numbers in Table 2 correspond to the derivative numbers in Table 1.

[Margin below] The rifamycin derivative represented by formula (I) according to the present invention also exhibits strong antibacterial activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis Mycobacterium tuberculosis
obacterius tuberculosis l
137Rv strain) was cultured in Dubos medium to prepare l mg/ml bacterial suspension, and 0.05 ml of the 10-fold dilution was inoculated into 2 ml of Klrchner liquid medium supplemented with lθ% bovine serum. did. For determination, prepare a multiple dilution series containing the test derivative according to the usual method,
After culturing at 37°C for 4 weeks, the concentration at which bacterial growth was completely inhibited macroscopically was defined as the minimum inhibitory concentration. 3rd result
Shown in Table and Table 4. The results shown here demonstrate that the novel rifamycin derivatives of the present invention exhibit strong antibacterial activity against Mycobacterium tuberculosis. Note that the derivative numbers in Tables 3 and 4 correspond to the derivative numbers in Table 1.

[Margin below] Table 4 The rifamycin derivative represented by formula (I) according to the present invention exhibits excellent therapeutic effects against experimental infections when administered orally. - As an example, the therapeutic effect of tuberculosis using mice will be shown.

Each group of 20 ddY male mice, aged 5 weeks, was used.

Mycobacterium tuberculosis (Mycobacterium tuberculosis) cultured in Dubos medium
lum tuberculosis t137Rv strain)
Concentrated bacteria solution 0.2ml (Number of live bacteria units 2.4X 108
) was inoculated into the tail vein of mice. Starting the day after infection, each test derivative was made into a 2.5% gum arabic suspension containing 0.296 Tveen 80 and orally administered in 0.2 ml portions, ie, 200 μg/mouse. The control contained 0.2% Tween 80 without the test compound2.
．． A 5% gum arabic solution was administered. Treatment is once a day.
The treatment was carried out 6 days a week, and the therapeutic efficacy was evaluated by prolonging the survival of infected mice.

The results are shown in FIG. In the figure, a indicates the time of infection, and b indicates the time of initiation of treatment. These results show that no deaths were observed in the treatment with Derivative 2 according to the present invention up to 38 days after treatment, and Derivative 2 was used as a control drug, and Fampicin, with the following structure described in US Pat. No. 4,890,919, was used as a control drug. It can be seen that it exhibits an extremely superior therapeutic effect compared to Derivative A. Also, derivative B having the following structure described in U.S. Patent No. 4.690.919 and European Patent Application No. 02533
Derivative C having the following structure described in specification No. 40
It has been shown in therapeutic trials that its therapeutic effect is not as good as that of rifampicin.

Shown in Tables 5 and 6.

Table 5 R1) Derivative A: R5-0IISRe -R8-H1R
8--C2H5 Furthermore, a treatment test for Mycobacterium tuberculosis infection was conducted in the same system as above using 10 ddY male mice per group.
The survival rate after 0 days was determined. In the experiment whose results are shown in Table 5, the survival rate was 30% in the control group in which no drug was administered;
Derivatives according to the invention 2.3.5.10.12 compared to 80% survival rate in the group treated with control drug Norifanpyrene.
No deaths were observed in the group administered with Or.29.

Table 6 In the experiment shown in Table 6, all of the control group to which no drug was administered died, and the survival rate of the group administered with the control drug Funubicin was 40%, whereas the survival rate of the derivatives 1.4. No deaths were observed in the groups administered with 6 or 11.

This result shows that the rifamycin derivative according to the present invention is an extremely effective drug against tuberculosis.

The novel rifamycin derivatives according to the present invention shown in Table 1 were orally administered to mice at a rate of 11,000II/kg, but no toxicity was shown, indicating that the novel rifamycin derivatives according to the present invention have low toxicity. It was.

As an antibacterial agent formulation containing the novel rifamycin derivative of the present invention as an active ingredient, any formulation for oral, enteral or parenteral administration can be selected.

Specific formulations include tablets, capsules, fine granules, syrups, crude drugs, and ointments. As carriers for the antimicrobial formulations according to the invention, organic or inorganic solid or liquid, usually inert, pharmaceutical carrier materials suitable for oral, rectal or other oral administration are used. Specific examples include crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols. The proportion of the antimicrobial agent of the invention to the carrier in the formulation can vary between 0.2 and 10%. The antimicrobial agent according to the invention can also include other antimicrobial agents and other pharmaceutical agents that are compatible therewith. In this case, it goes without saying that the antibacterial agent according to the present invention does not have to be the main ingredient in the preparation.

Antimicrobial agents according to the invention are generally administered at dosages that achieve the desired effect without side effects. The specific value should be determined by a doctor's judgment, but it is generally 10 mg to 10 g, preferably 20 mg to 5 g per adult.
It would normally be administered at a dose of about 1.5 g. The antibacterial agent of the present invention has an active ingredient of IB ~ 5g, preferably 3B ~
It can be administered as a pharmaceutical preparation in units of 1 g.

[Examples] In order to further clarify the understanding of the present invention, examples will be described below, but these are merely illustrative and do not limit the present invention. Note that the numbers of the derivatives in the examples correspond to the derivative numbers in Table 1.

Example 1 (Synthesis of Derivative 1) 8.0 g of 3°-hydroxybenzoxazinorifamycin synthesized according to the method described in US Pat. No. 4,890,919 was added to 80 ml of dimethyl sulfoxide (hereinafter referred to as DMSO). Dissolved and added a solution of 2.85 g of 1-n-butylpiperazine in 20 ml of DMSO. 9.0 g of manganese dioxide was added to this solution, and the mixture was stirred and reacted at room temperature for 40 hours. Add 600% ethyl acetate to the reaction solution.
After dilution, manganese dioxide was removed by filtration. The filtrate was washed three times with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Wakogel the residue ■C
-200 silica gel column chromatography twice [Developing solvent = 1st time chloroform acetone (4
:l), second chloroform-methanol (50:l)
)] After purification, crystallization was performed from an ethyl acetate-n-hexane system to obtain 3.58 g of the desired derivative 1.

Example 2 (Synthesis of derivative 2) 3′-Hydroxybenzoxazinorifamycin 3.0
Dissolve 1.05 g of l-inbutylpiperazine in 30 ml of DNSo, then add 3.0 g of manganese dioxide.
0 g was added, and the mixture was stirred and reacted at room temperature for 25 hours.

After adding ethyl acetate to the reaction solution and filtering off manganese dioxide, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. Wakogel the residue ■C
After purification by silica gel column chromatography using -200 [developing solvent: chloroform-acetone (8:2)], 0.82 g of derivative 2 was obtained by crystallization from an ethyl acetate-〇-hexane system.

Example 3 (Synthesis of derivative 3) 3′-Hydroxybenzoxazinorifamycin 6.
0 g was dissolved in 60 ml of DNSo, 2.13 g of 1-cyclopropylmethylbiverazine was added, and then 6.0 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 30 hours. After the reaction solution was treated in the same manner as in Example 2, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-acetone (8:2
)] to obtain 4.0 g of derivative 3.

Example 4 (Synthesis of derivative 4) 3°-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45 ml of DNSo, 1.58 g of 1-see-butylpiperazine was added, and then 4.5 g of manganese dioxide was added, and the mixture was reacted with stirring at room temperature for 22 hours.

After treating the reaction solution in the same manner as in Example 2, the residue was transferred to Wakogel ■
Twice by silica gel column chromatography using C-200 [Developing solvent: once chloroform-acetone (
li:2), second chloroform-methanol (98
:2)] to obtain 3.9 g of the desired derivative 4.

Example 5 (Synthesis of derivative 5) 3”-hydroxybenzoxazinorifamycin 8.0
g was dissolved in 80 ml of DNSo, and a solution of 3.13 g of ■-isoamylpiperazine dissolved in 20 ml of DMSO was added. 9.0 g of manganese dioxide was added to this solution, and the mixture was stirred and reacted at room temperature for 40 hours. After the reaction solution was treated in the same manner as in Example 1, the residue was subjected to silica gel column chromatography using Wako Gel ■C-200 three times [developing solvent: 1st time chloroform-acetone (5:1), 2nd time chloroform-ethyl acetate (2 :1), 3rd time chloroform-ethyl acetate-methanol (I5:1O:1)
] After purification, 3.38 g of derivative 5 was obtained by crystallization from a chloroform-n-hexane system.

Example 6 (Synthesis of derivative 6) 3°-Hydroxybenzoxazinorifamycin 4.
Dissolve 38 g in 30 ml of DNSo, add 1-tert
-Butylpiperazine3. lOg and manganese dioxide 1.0
g was added thereto, and the mixture was stirred and reacted at room temperature for 21 hours. The reaction solution was diluted with chloroform, and insoluble matter was filtered off. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then chloroform was distilled off under reduced pressure. Wakogel ■C-
Silica gel column chromatography using 200 [
Developing solvent: chloroform-methanol (98:2)], and then crystallized from ethyl acetate-n-hexane.
2.97 g of the desired derivative 6 was obtained.

Example 7 (Synthesis of derivative 7) 3°-Hydroxybenzoxazinorifamycin 4.3
Dissolve 8 g in 30 ml of DNSo, add 3.08 g of -cyclobutylpiperazine and manganese dioxide 1. Og was added and the mixture was stirred and reacted at room temperature for 17 hours. The reaction mixture was diluted with chloroform, and insoluble matter was filtered off. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then chloroform was distilled off under reduced pressure. Wakogel [F]C the residue
-200 silica gel column chromatography [developing solvent: chloroform-methanol (99:l)]
was purified, and then crystallized from chloroform-n-hexane to obtain 2.77 g of the desired derivative 7.

Example 8 (Synthesis of derivative 8) 3"-Hydroxybenzoxazinorifamycin 2.6
Dissolve g in 20 ml of DMSO, add 2.04 g of l-neopentylpiperazine, and then add 0.5 g of manganese dioxide.
was added, and the mixture was stirred and reacted at room temperature for 67 hours. After adding chloroform to the reaction solution and filtering off manganese dioxide, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using Wakogel C-200 five times [developing solvent = 1.2 and the fifth chloroform:methanol (99%).
), 3rd chloroform:methanol (I99:l)
4th ethyl acetate: n-hexane (Ill, )]
After purification, 0.44 g of the desired derivative 8 was obtained.

Example 9 (Synthesis of derivative 9) 3′-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45 ml of DNSo, 1.7 g of ■-cyclopentylpiperazine was added thereto, and then 4.5 g of manganese dioxide was added thereto, and the mixture was stirred and reacted at room temperature for 19 hours. After adding chloroform to the reaction solution and filtering off manganese dioxide, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. After purifying the residue by silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (98:2)],
Crystallization from ethanol yielded 2.8 g of derivative 9.

Example IO (Synthesis of derivative IO) 3°-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in 40 ml of DNSo, 1.39 g of ■-allylpiperazine was added, and then 4.5 g of manganese dioxide
g, and the mixture was stirred and reacted at room temperature for 25 hours. After treating the reaction solution in the same manner as in Example 8, the residue was purified by Wakogel [F]C-2.
4 by silica gel column chromatography using 00 [developing solvent: chloroform-methanol (95:5)].
The product was purified twice to obtain 2.7 g of derivative 10.

Example 11 (Synthesis of derivative 11) 3°-Hydroxybenzoxazinorifamycin 4.5
Dissolve g in 45 ml of DMSO to obtain 1-(3-butenyl)
Add 2.0 g of piperazine and then add 4.5 g of manganese dioxide.
g was added thereto, and the mixture was stirred and reacted at room temperature for 23.5 hours. After adding chloroform to the reaction solution and filtering off manganese dioxide, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure.

The residue was purified twice by silica gel column chromatography using Wakogel ■C-200 [developing solvent: 1st time chloroform-acetone (8:2), 2nd time chloroform-methanol (99:1)]] and then purified with loloform-nhexane. Crystallize the desired derivative 11 from the system of 3.38
I got g.

Example 12 (Synthesis of derivative 12) 3°-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45 ml of DNSo, 1.69 g of 1-(3-methyl-2-butenyl)piperazine was added, and then 4.5 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 28 hours. After treating the reaction solution in the same manner as in Example 2, the residue was purified twice by silica gel column chromatography using Wako Gel C-200 [developing solvent = 1st time chloroform-methanol (98:2), 20th time ethyl acetate]. Further, crystallization was performed using an ethyl acetate-n-hexane system to obtain 1.8 g of derivative 12.

Example 13 (Synthesis of derivative 13) 3'-hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45a+1 DMSO, 2.7 g of 1-(2-propynyl)piperazine was added thereto, 4.5 g of manganese dioxide was added thereto, and the mixture was stirred and reacted at room temperature for 123.5 hours.

After adding chloroform to the reaction solution and filtering out manganese dioxide,
The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography using Wakogel C-200 four times [developing solvent: 1 to 3 times chloroform-methanol (98:2), 4 times chloroform-acetone (9:1)]]. 1. The desired derivative 13 was crystallized from the loloform-nhexane system.
Obtained 57g.

Example 14 (Synthesis of derivative 14) 3°-Hydroxybenzoxazinorifamycin 4.5
Dissolve 1.g of 1-(2-fluoroethyl)piperazine in 45 ml of DMSO. Og was added thereto, and then 4.5 g of manganese dioxide was added, followed by stirring and reaction at room temperature for 96 hours.

After adding chloroform to the reaction solution and filtering out manganese dioxide,
The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography using Wako Gel ■C-200 four times [developing solvent = chloroform-methanol (98:2) for the first to third times, chloroform-methanol (98:2) for the fourth time], and then purified with loloform-n. The desired derivative 14 was crystallized from a hexane system at a concentration of 0.
48g was obtained.

Example 15 (Synthesis of derivative 15) 3-hydroxybenzoxazinorifamycin 2.0 g
was dissolved in 20 ml of DNSo, 1.22 g of 1-(3-chloropropyl)biverazine dihydrochloride hemihydrate was added, and then 2.8 g of triethylamine was added.
ml and manganese dioxide2. Of was added, and the mixture was stirred and reacted at room temperature for 5 hours. After treating the reaction solution in the same manner as in Example 9,
The residue was purified three times by silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-acetone (8:2)], and then crystallized from ethyl acetate to obtain 0.6 g of derivative 15.

Example 16 (Synthesis of derivative 16) 3′-Hydroxybenzoxazinorifamycin 2.7
Dissolve 1.g of 1-(2-dimethylaminoethyl)piperazine in 27ml of DMSO. Then, 2.7 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 122 hours. After adding chloroform to the reaction solution and filtering off manganese dioxide, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. The residue is Wakogel [F
] Four times by silica gel column chromatography using C-200 [Developing solvent: chloroform-methanol (9
:L) ] Purified to obtain 0.57 g of the desired derivative 1B.

Example 17 (Synthesis of derivative 17) 3'-hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45 ml of DMSO, 2.0 g of 1-(2-diethylaminoethyl)piperazine was added, and then 4.5 g of manganese dioxide was added, and the mixture was reacted with stirring at room temperature for 27 hours. Methanol was added to the reaction solution, manganese dioxide was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified five times by silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (95:5)] to obtain 0.82 g of the desired derivative 17.

Example 18 (Synthesis of derivative I8) 3°-Hydroxybenzoxazinorifamycin 4.5
2.6 g of -(2-pyrimidyl)biperazine dihydrochloride was added, and then 3.1 ml of triethylamine was dissolved in 45 ml of DMSO.
5 g was added, and the mixture was stirred and reacted at room temperature for 24 hours.

After adding chloroform to the reaction solution and filtering out manganese dioxide,
The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure.

The residue was purified three times by silica gel column chromatography using Wakogel C-200 [developing solvent: chloroform-methanol (49:l)], and then crystallized from a chloroform-〇-hexane system to obtain the desired derivative I8. 2.
85g was obtained.

Example 19 (Synthesis of derivative 19) 3°-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in DM'3045 ml, 1.59 g of ■-(2-methoxyethyl)piperazine was added thereto, and then 4.5 g of manganese dioxide was added thereto, and the mixture was stirred and reacted at room temperature for 51 hours. After treating the reaction solution in the same manner as in Example 2, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (98:
2)] and then crystallized from a chloroform-〇-hexane system to obtain 1.2 g of derivative I9.

Example 20 (Synthesis of derivative 20) 1.8 g of 3-hydroxybenzoxazinorifamycin
was dissolved in 18 ml of DMSO, 1.4 g of ■-(2-ethoxyethyl)piperazine was added, and then 1.8 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 120 hours. After treating the reaction solution in the same manner as in Example 7, the residue was treated with Wakogel ■C.
Silica gel column chromatography using -200 [developing solvent: chloroform-methanol (98:2)]
After purification twice, crystallization was performed from an ethyl acetate-〇-hexane system to obtain 0.5 g of derivative 20.

Example 21 (Synthesis of derivative 21) 3′-hydroxybenzoxazinorifamycin 4.5
Dissolve g in 45 ml of DMSO, add 2.1 g of l-[(2-methoxy)-2-ethoxyethylcopiperazine,
Next, 4.5 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 28.5 hours. After adding chloroform to the reaction solution and filtering off manganese dioxide, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography-Q using Wakogel C-200 twice [developing solvent: chloroform-methanol (98:2)], and then crystallized from a loloform-hexane system to obtain the desired derivative 21. 0.7
I got 2g.

Example 22 (Synthesis of derivative 22) 3′-Hydroxybenzoxazinorifamycin 4.5
g was dissolved in 45 ml of DMSo, 1.89 g of 1-(I,3-dioxolan-2-yl)methylbiperazine was added, and then 4.5 f of manganese dioxide was added, and the solution was dissolved at room temperature for 2 hours.
The reaction was stirred for 6 hours. After treating the reaction solution in the same manner as in Example 9, the residue was subjected to silica gel column chromatography using Wakogel ■C-2QO [developing solvent: chloroform-
After purification twice with methanol (98:2)], crystallization was performed from ethyl acetate to obtain 2.7 g of derivative 22.

Example 23 (Synthesis of derivative 23) 1.8 g of 3-hydroxybenzoxazinorifamycin
was dissolved in 18 ml of DNSo, 0.5 g of ■-formylpiperazine was added, and then 1.8 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 24 hours.

After the reaction solution was treated in the same manner as in Example 9, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (98:
2)] and then crystallized from a chloroform-n-hexane system to obtain 0.9 g of derivative 23.

Example 24 (Synthesis of derivative 24) 3'-hydroxybenzoxazinorifamycin 4.5
Dissolve g in 45 ml of DNSo, add 1.4 g of l-acetylpiperazine, and then add 4.5 g of manganese dioxide.
was added, and the mixture was stirred and reacted at room temperature for 22 hours.

After treating the reaction solution in the same manner as in Example 9, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [Developing solvent: chloroform-methanol (9 g:
2)] to obtain 3.2 g of derivative 24.

Example 25 (Synthesis of derivative 25) 3-hydroxybenzoxazinorifamycin 3.0
fr was dissolved in DMSO30 (!11), 1.3 g of ■-cyclobrobancarponylpiverazine was added, and then 2.0 g of manganese dioxide was added and the reaction was stirred at room temperature for 22 hours. The reaction solution was prepared in the same manner as in Example 9. After treatment, the residue was subjected to silica gel column chromatography using Wako Gel C-200 three times [developing solvent: 1st chloroform-methanol (99:1), 2nd chloroform-methanol (98:2), 3rd chloroform-methanol Acetone (95:
5)] was purified to obtain 2.0 g of derivative 25.

Example 2B (Synthesis of derivative 2B) 3°-Hydroxybenzoxazinorifamycin 1.8
Dissolve g in 18 ml of DNSO, N-isopropyl-
0.112 g of 1-piperazine acetamide was added, and then manganese dioxide t, sg was added, and the mixture was stirred and reacted at room temperature for 27 hours. After treating the reaction solution in the same manner as in Example 9,
The residue was subjected to silica gel column chromatography using Wakogel [F]C-200 [developing solvent: chloroform-
After purification with methanol (98:2)], 1.4 g of derivative 26 was obtained by crystallization from ethyl acetate.

Example 27 (Synthesis of derivative 27) 3°-Hydroxybenzoxazinorif 7mycin 4.5
g was dissolved in 45 ml of DMSO, 1.9 g of 1-(2-ethylthioethyl)piperazine was added thereto, then 4.5 g of manganese dioxide was added thereto, and the mixture was stirred and reacted at room temperature for 23 hours.

After adding chloroform to the reaction solution and filtering out manganese dioxide,
The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate overnight, and the solvent was distilled off under reduced pressure. Wakogel the residue ■C
6 times by silica gel column chromatography using -200 [Developing solvent: chloroform-methanol (98:2) for 1st to 5th times, chloroform-acetone (4: 6th time)
1)] was purified to obtain 3.0 Og of the desired derivative 27.

Example 28 (Synthesis of derivative 28) 3′-Hydroxybenzoxazinorifamycin 2.
Dissolve 83 g in 15 ml of DNSo, add 0.76 g of ■-methoxypiperazine and 1.5 g of manganese dioxide. Og was added and the mixture was stirred and reacted at room temperature for 3 days. The 1-methoxypiverazine used here was prepared according to the synthesis of l-cyclopropylviverazine described in U.S. Pat. No. 3,342.81[i]. -Synthesized from toluenesulfonamide and O-methylhydroxylamine. The reaction solution was diluted with chloroform, insoluble matter was filtered off, the filtrate was washed successively with water and saturated brine, and chloroform was distilled off under reduced pressure. Wakogel the residue ■C
-200 silica gel column chromatography twice [Developing solvent: 1st time chloroform acetone (9
5:5), second chloroform-methanol (98:2)
)] and then precipitated from ethyl acetate-〇-hexane to obtain 1.71 g of the desired derivative 28.

Example 29 (Synthesis of derivative 29) 3°-Hydroxybenzoxazinorifamycin 1.8
Dissolve g in DNSo 18 ml, M, E, Fre
The method of ed et al. [Journal of Organic Chemistry (J, Org, Chcv,), vol. 25, 21
08, 1960] was added, followed by 1.8 g of manganese dioxide, and the mixture was stirred and reacted at room temperature for 52 hours.

After treating the reaction solution in the same manner as in Example 2, the residue was purified by Wakogel [
F] Silica gel column chromatography using C-200 [Developing solvent: chloroform-methanol (98:
2)] five times to obtain 0.3 g of derivative 29.

Example 30 (Synthesis of derivative 30) 3°-Hydroxybenzoxazinorifamycin 1.8
g was dissolved in 18 ml of DNSo, 1.0 g of 3-dimethylaminopyrrolidine was added, and then manganese dioxide i and g were added, and the mixture was stirred and reacted at room temperature for 140 hours. After the reaction solution was treated in the same manner as in Example 7, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (98%
:2)] four times to obtain 0.5 g of derivative 30.

Example 31 (Synthesis of derivative 31) 3°-Hydroxybenzoxazinorifamycin 1.8
g was dissolved in 18 ml of DNSo, 0.56 g of 3-acetamidopyrrolidine was added, and then 1.8 g of manganese dioxide was added, and the mixture was stirred and reacted at room temperature for 47 hours. After the reaction solution was treated in the same manner as in Example 9, the residue was subjected to silica gel column chromatography using Wakogel ■C-200 [developing solvent: chloroform-methanol (95:5
)] three times to obtain 0.8 g of derivative 31.

Example 32 (Synthesis of derivative 32) A mixed solution of 90 ml of ethanol and 90 ml of water was cooled with ice water, and 0.913 g of sodium hydroxide was dissolved therein. Derivative 2 synthesized according to the method shown in Example 2 in the mixed solution 1.
05 g was added thereto, and the mixture was stirred and reacted at room temperature for 2 hours. 40 ml of cold water was added to the reaction solution, neutralized with IN-HCN, extracted three times with 40 ml of chloroform, and the solvent was distilled off under reduced pressure.

The residue was purified three times by silica gel column chromatography using Wakogel C-200 [developing solvent: chloroform-methanol (99:1)] to obtain the desired derivative 3.
0.70g of 2 was obtained.

[Effects of the Invention] The novel rifamycin derivatives of the present invention have strong antibacterial effects and excellent pharmacological properties.

It is a graph showing the relationship between.

[Brief explanation of the drawing]

Figure 1 shows the survival rate of mice with tuberculosis, the number of days of treatment, and the number of days of treatment when the Norifamycin derivative of the present invention and other test compounds were orally administered to mice with tuberculosis.

Claims (1)

[Claims] 1 Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a hydrogen atom or an acetyl group, and A is a formula ▲A mathematical formula, a chemical formula, a table, etc.) ▼ [In the formula, R^1 is an alkyl group having 4 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, or an aminoalkyl group having 2 to 4 carbon atoms. -6 monoalkylaminoalkyl group, dialkylaminoalkyl group having 3 to 8 carbon atoms,
Alkoxyalkyl group having 2 to 8 carbon atoms, alkoxyalkyloxyalkyl group having 3 to 8 carbon atoms, thioalkoxyalkyl group having 2 to 6 carbon atoms, dialkoxyalkyl group having 3 to 8 carbon atoms, and dialkoxyalkyl group having 1 to 6 carbon atoms. halogenated alkyl group,
Acyl group having 1 to 6 carbon atoms, formula: -(CH_2)_a-CONHR^2 (wherein a is 0 to
represents an integer of 3, and R^2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), a group having 1 carbon number
~3 Alkoxy group or formula: ▲There are numerical formulas, chemical formulas, tables, etc. ▼ Represents the group shown] Group or formula: ▲There are numerical formulas, chemical formulas, tables, etc.▼ (In the formula, b is 2 to (Representing an integer of 6): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n represents an integer of 2 to 6, and R^3 is an amino group, with a carbon number of 1 to 6. a monoalkylamino group, a dialkylamino group having 2 to 10 carbon atoms, or an acylamino group having 1 to 6 carbon atoms} or a salt thereof. 2. The rifamycin derivative or salt thereof according to claim 1, wherein in the formula (I), R is an acetyl group. 3. The rifamycin derivative or salt thereof according to claim 1, wherein in the formula (I), R is a hydrogen atom. 4 In the above formula (I), R is an acetyl group,
A is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R
^4 represents an alkyl group having 4 to 8 carbon atoms or an alkenyl group having 2 to 8 carbon atoms): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, b is an alkyl group having 2 to 6 carbon atoms) The rifamycin derivative or salt thereof according to claim 1, which is a group represented by (representing an integer). 5 In the above formula (I), R is an acetyl group,
The rifamycin derivative or its salt according to claim 1, wherein A is a group represented by the formula: ▲ Numerical formula, chemical formula, table, etc. ▼. 6 In the above formula (I), R is an acetyl group,
The rifamycin derivative or its salt according to claim 1, wherein A is a group represented by the formula: ▲ Numerical formula, chemical formula, table, etc. ▼. 7 In the above formula (I), R is an acetyl group,
The rifamycin derivative or its salt according to claim 1, wherein A is a group represented by the formula: ▲ Numerical formula, chemical formula, table, etc. ▼. 8 In the above formula (I), R is an acetyl group,
The rifamycin derivative or its salt according to claim 1, wherein A is a group represented by the formula: ▲ Numerical formula, chemical formula, table, etc. ▼. 9 Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R represents a hydrogen atom or an acetyl group) The rifamycin derivative represented by the formula AH {wherein A is the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an alkyl group having 4 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or 1 to 4 carbon atoms. aminoalkyl group, monoalkylaminoalkyl group having 2 to 6 carbon atoms, dialkylaminoalkyl group having 3 to 8 carbon atoms, alkoxyalkyl group having 2 to 8 carbon atoms, alkoxyalkyloxyalkyl group having 3 to 8 carbon atoms, Thioalkoxyalkyl group having 2 to 6 carbon atoms, dialkoxyalkyl group having 3 to 8 carbon atoms, halogenated alkyl group having 1 to 6 carbon atoms, acyl group having 1 to 6 carbon atoms, formula: -(CH_2)_a- CONHR^2 (in the formula, a is 0~
represents an integer of 3, and R^2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), a group having 1 carbon number
~3 Alkoxy group or formula: ▲There are numerical formulas, chemical formulas, tables, etc. ▼ Represents the group shown] Group or formula: ▲There are numerical formulas, chemical formulas, tables, etc.▼ (In the formula, b is 2 to (Representing an integer of 6) or formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n represents an integer of 2 to 6, and R^3 is an amino group, with a carbon number of 1 to 6.) 6 monoalkylamino group, dialkylamino group having 2 to 10 carbon atoms, or acylamino group having 1 to 6 carbon atoms). ): ▲Mathematical formulas, chemical formulas, tables, etc. ▼(I) A method for producing a rifamycin derivative represented by (in the formula, R and A are the same as above). 10. The production method according to claim 9, wherein the rifamycin derivative represented by formula (II) is reacted with an amine represented by formula AH (wherein A is the same as above) in the presence of an oxidizing agent. 11. The production method according to claim 10, wherein the oxidizing agent is manganese dioxide. 12 R characterized by hydrolyzing a rifamycin derivative represented by formula (I) in which R is an acetyl group
A method for producing a rifamycin derivative represented by formula (I), wherein is a hydrogen atom. 13. The production method according to claim 12, wherein the reagent used for hydrolysis is an alkali metal hydroxide. 14 Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R represents a hydrogen atom or an acetyl group, and A is the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an alkyl group having 4 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, or a monoalkylamino group having 2 to 6 carbon atoms. Alkyl group, dialkylaminoalkyl group having 3 to 8 carbon atoms,
Alkoxyalkyl group having 2 to 8 carbon atoms, alkoxyalkyloxyalkyl group having 3 to 8 carbon atoms, thioalkoxyalkyl group having 2 to 6 carbon atoms, dialkoxyalkyl group having 3 to 8 carbon atoms, and dialkoxyalkyl group having 1 to 6 carbon atoms. halogenated alkyl group,
Acyl group having 1 to 6 carbon atoms, formula: -(CH_2)_a-CONHR^2 (wherein a is 0 to
represents an integer of 3, and R^2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), a group having 1 carbon number
~3 Alkoxy group or formula: ▲There are numerical formulas, chemical formulas, tables, etc. ▼Represents the group shown]; ▲There are numerical formulas, chemical formulas, tables, etc.▼ (where b is 2 to (Representing an integer of 6): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n represents an integer of 2 to 6, and R^3 is an amino group, with a carbon number of 1 to 6. a monoalkylamino group, a dialkylamino group having 2 to 10 carbon atoms, or an acylamino group having 1 to 6 carbon atoms) or a pharmacologically acceptable salt thereof. Antibacterial agent as an active ingredient.